Indole derivatives as 5-HT1 agonists

ABSTRACT

Compounds of the formula (I) where A represents a direct bond, C 1  -C 4  alkyl, or C 1  -C 4  alkenyl; n is 0, 1, or 2; W, X, Y, and Z are each independently oxygen, sulfur, nitrogen or carbon, provided that at least one of W, X, Y, or Z is nitrogen. These compounds are useful psychotherapeutics and are potent serotonin (5-HT 1 ) agonists and may be used in the treatment of depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders, and other disorders arising from deficient serotonergic neurotransmission. The compounds can also be used as centrally acting antihypertensives and vasodilators.

This application is a 371 of PCT/US93/01667 filed Mar. 3, 1993.

BACKGROUND OF THE INVENTION

The present invention relates to indole derivatives, to processes andintermediates for their preparation, to pharmaceutical compositionscontaining them and to their medicinal use. The active compounds of thepresent invention are useful in treating migraine and other disorders.

U.S. Pat. Nos. 4,839,377 and 4,855,314 and European Patent ApplicationPublication Number 313397 refer to 5-substituted 3-aminoalkyl indoles.The compounds are said to be useful for the treatment of migraine.

British Patent Application 040279 refers to3-aminoalkyl-1H-indole-5-thioamides and carboxamides. The compounds aresaid to be useful in treating hypertension, Raymond's disease andmigraine.

European Patent Application Publication Number 303506 refers to3-poly:hydropyridyl-5-substituted-1H-indoles. The compounds are said tohave 5-HT₁ receptor agonist and vasoconstrictor activity and to beuseful in treating migraine.

European Patent Application Publication Number 35477 refers toN-piperidinyl:indolyl:ethyl-alkane sulfonamide derivatives. Thecompounds are said to have 5-HT₁ receptor agonist and vasoconstrictoractivity and to be useful in treating cephalic pain.

European Patent Application Publication Numbers 438230, 494774, and497512 refer to indole-substituted five-membered heteroaromaticcompounds. The compounds are said to have 5-HT₁ -like receptor agonistactivity and to be useful in the treatment of migraine and otherdisorders for which a selective agonist of these receptors is indicated.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2## whereA represents a direct bond, C₁ -C₄ alkyl, or C₁ -C₄ alkenyl; n is 0, 1,or 2; R₁ is hydrogen, C₁ -C₆ alkyl, aryl, C₁ -C₃ alkylaryl, C₁ -C₃alkylheteroaryl, or --(CH₂)_(m) R₆ ; W, X, Y, and Z are eachindependently oxygen, sulfur, nitrogen or carbon, provided that at leastone of W, X, Y, or Z is nitrogen; R₂, R₃, R₄, and R₅ are eachindependently hydrogen, C₁ -C₆ alkyl, aryl, C₁ -C₃ alkylaryl, C₁ -C₃alkylheteroaryl, halogen, cyano, trifluoromethyl, nitro, --OR₇, --NR₇R₈, --(CH₂)_(s) OR₇, --SR₇, --SO₂ NR₇ R₈, --NR₇ SO₂ R₈, --NR₇ CO₂ R₈,--CONR₇ R₈, or --CO₂ R₇ ; one of R₂ and R₃, R₃ and R₄, or R₄ and R₅ maybe taken together to form a five- to seven-membered alkyl ring, aSix-membered aryl ring, a five- to seven-membered heteroalkyl ringhaving 1 heteroatom of N, O, or S, or a five- to six-membered heteroarylring having 1 or 2 heteroatoms of N, O or S; R₆ is cyano,trifluoromethyl, or --OR₉ ; R₇, R₈, and R₉ are each independentlyhydrogen, C₁ to C₆ alkyl, --(CH₂)_(m) R₁₀, C₁ to C₃ alkylaryl, or aryl;R₇ and R₈ may be taken together to form a C₄ -C₇ alkyl ring; R₁₀ iscyano, trifluoromethyl, or C₁ -C₄ alkoxy; R₁₁ is hydrogen, --OR₁₂, or--NHCOR₁₂ ; R₁₂ is C₁ to C₆ alkyl, aryl, or C₁ to C₃ alkyl-aryl; m is 1,2, or 3; s is 0, 1, 2, or 3; and the above aryl groups and the arylmoieties of the above alkylaryl groups are independently selected fromphenyl and substituted phenyl, wherein said substituted phenyl may besubstituted with one to three groups selected from C₁ to C₄ alkyl,halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano,carboxamido, nitro, and C₁ to C₄ alkoxy, and the pharmaceuticallyacceptable salts thereof. These compounds are useful in treatingmigraine and other disorders.

The compounds of the invention include all optical isomers of formula I(e.g., R and S stereogenicity at any chiral site) and their racemic,diastereomeric, or epimeric mixtures. When R₁₁ is hydrogen, the epimerswith the R absolute configuration at the chiral carbon site designatedby an asterisk in formula I are preferred. When R₁₁ is --OR₁₂ or--NHCOR₁₂ and n is 0 or 1, the epimers with the S absolute configurationat the chiral carbon site designated by an asterisk in formula I arepreferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 2, the epimers withthe R absolute configuration at the chiral carbon site designated by anasterisk in formula I are preferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ andn is 0, the cis epimers [(2S, 3S) absolute configuration in theazetidine ring] are particularly preferred. When R₁₁ is --OR₁₂ or--NHCOR₁₂ and n is 1, the cis epimers [(2S, 4R) absolute configurationin the pyrrolidine ring] are particularly preferred. When R₁₁ is --OR₁₂or --NHCOR₁₂ and n is 2, the cis epimers [(2R, 5R) absoluteconfiguration in the piperidine ring] are particularly preferred.

Unless otherwise indicated, the alkyl groups referred to herein, as wellas the alkyl moieties of other groups referred to herein (e.g. alkoxy),may be linear or branched, and they may also be cyclic (e.g.cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear orbranched and contain cyclic moieties.

Preferred compounds of the invention are compounds of the formula Iwherein A is either a direct bond or --CH₂ --; n is 1; R₁ is hydrogen,C₁ -C₄ alkyl or --CH₂ CH₂ OCH₃ ; Z is nitrogen; Y is carbon; W and X areeach independently oxygen, sulfur, nitrogen or carbon; and R₂, R₃, andR₄ are as defined above. Of the foregoing preferred compounds, when R₁₁is hydrogen, the epimers with the R absolute configuration at the chiralcarbon site designated by an asterisk in formula I are more preferred.Of the foregoing preferred compounds, when R₁₁ is --OR₁₂ or --NHCOR₁₂,the epimers with the S absolute configuration at the chiral carbon sitedesignated by an asterisk in formula I are more preferred. Of theforegoing compounds, when R₁₁ is --OR₁₂ or --NHCOR₁₂, the cis epimers[(2S, 4R) absolute configuration in the pyrrolidine ring] areparticularly preferred.

The following compounds are particularly preferred:

(R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(3-benzyl-1,2,4-oxadiazol-5yl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;

(R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;and

(R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole.

The present invention also relates to a pharmaceutical composition fortreating a condition selected from hypertension, depression, anxiety,eating disorders, obesity, drug abuse, cluster headache, migraine, pain,and chronic paroxysmal hemicrania and headache associated with vasculardisorders comprising an amount of a compound of the formula I or apharmaceutically acceptable salt thereof effective in treating suchcondition and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treating a conditionselected from hypertension, depression, anxiety, eating disorders,obesity, drug abuse, cluster headache, migraine, pain and chronicparoxysmal hemicrania and headache associated with vascular disorderscomprising administering to a mammal (e.g., a human) requiring suchtreatment an amount of a compound of the formula I or a pharmaceuticallyacceptable salt thereof effective in treating such condition.

The present invention also relates to a pharmaceutical composition fortreating disorders arising from deficient serotonergic neurotransmission(e.g., depression, anxiety, eating disorders, obesity, drug abuse,cluster headache, migraine, pain and chronic paroxysmal hemicrania andheadache associated with vascular disorders) comprising administering toa mammal (e.g., a human) requiring such treatment an amount of acompound of the formula I or a pharmaceutically acceptable salt thereofeffective in treating such condition.

The present invention also relates to a method for treating disordersarising from deficient serotonergic neurotransmission (e.g., depression,anxiety, eating disorders, obesity, drug abuse, cluster headache,migraine, pain and chronic paroxysmal hemicrania and headache associatedwith vascular disorders) comprising administering to a mammal (e.g., ahuman) requiring such treatment an amount of a compound of the formula Ior a pharmaceutically acceptable salt thereof effective in treating suchcondition.

The present invention also relates to a compound of the formula ##STR3##where n, A, W, X, Y, Z, R₂, R₃, R₄, R₅, and R₁₁ are as defined above;and R₁₃ is C₁ -C₆ alkyl, aryl, or alkylaryl (preferably benzyl). WhenR₁₁ is hydrogen, the epimers with the R absolute configuration at thechiral carbon site designated by an asterisk in formula II arepreferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 0 or 1, the epimerswith the S absolute configuration at the chiral carbon site designatedby an asterisk in formula II are preferred. When R₁₁ is --OR₁₂ or--NHCOR₁₂ and n is 2, the epimers with the R absolute configuration atthe chiral carbon site designated by an asterisk in formula II arepreferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 0, the cis epimers[(2S, 3S) absolute configuration in the azetidine ring] are particularlypreferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 1, the cis epimers[(2S, 4R) absolute configuration in the pyrrolidine ring] areparticularly preferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 2, thecis epimers [(2R, 5R) absolute configuration in the piperidine ring] areparticularly preferred. The compounds of formula II are useful asintermediates in preparing compounds of formula I.

The present invention also relates to a compound of the formula ##STR4##where n, A, W, X, Y, Z, R₂, R₃, R₄, R₅, R₁₁ and R₁₃ are as definedabove; R₁₄ is halogen (e.g. fluorine, chlorine, bromine, or iodine[preferably bromine or iodine]); and R₁₅ is --COCF₃, --SO₂ CH₃, --SO₂ Ph[Ph=phenyl], or --CO₂ C(CH₃)₃ [preferably --COCF₃ ]. When R₁₁ ishydrogen, the epimers with the R absolute configuration at the chiralcarbon site designated by an asterisk in formula III are preferred. WhenR₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 0 or 1, the epimers with the Sabsolute configuration at the chiral carbon site designated by anasterisk in formula III are preferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂and n is 2, the epimers with the R absolute configuration at the chiralcarbon site designated by an asterisk in formula III are preferred. WhenR₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 0, the cis epimers [(2S, 3S)absolute configuration in the azetidine ring] are particularlypreferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 1, the cis epimers[(2S, 4R) absolute configuration in the pyrrolidine ring] areparticularly preferred. When R₁₁ is --OR₁₂ or --NHCOR₁₂ and n is 2, thecis epimers [(2R, 5R) absolute configuration in the piperidine ring] areparticularly preferred. The compounds of formula III are useful asintermediates in preparing compounds of formula II.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are prepared via the followingreaction scheme. ##STR5##

Compounds of formula III can be prepared by the Mitsunobu couplingreaction of compounds of formulas IV and V wherein n, A, W, X, Y, Z, R₂,R₃, R₄, R₅, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are as defined above using aphosphine and an azodicarboxylate in a suitable solvent. Suitablephosphines include trialkyl phosphines and triarylphosphines, preferablytriphenylphosphine. Suitable azodicarboxylates include dialkylazodicarboxylates, preferably diethyl diazodicarboxylate. Suitablesolvents include methylene chloride, ethers, (tetrahydrofuran, diethylether, and 1,4-dioxane), N,N-dimethylformamide and acetonitrile. Thepreferred solvent is tetrahydrofuran. The reaction is conducted at atemperature of from about 0° C. to about 65° C., most preferably atabout 25° C.

Compounds of formula II can be prepared by the transition metalcatalyzed cyclization of compounds of the formula III where n, A, W, X,Y, Z, R₂, R₃, R₄, R₅, R₁₁, and R₁₃ are as defined above, R₁₄ is halogen(preferably bromine or iodine) and R₁₅ is --COCF₃, --SO₂ CH₃, --SO₂ Ph,or --CO₂ C(CH₃)₃, preferably trifluoromethylacetyl [--COCF₃ ], in asuitable inert solvent with a phase transfer catalyst and a base.Suitable catalysts include palladium salts such as palladium (11)acetate or palladium (11) chloride (preferably palladium acetate) andrhodium salts, such as tris(triphenyl)rhodium (I) chloride. Suitablesolvents include N,N-dimethylformamide, acetonitrile, andN-methylpyrrolidine. The preferred solvent is N,N-dimethylformamide.Suitable phase transfer catalysts include tetraalkylammonium halides,and tetra-n-butylammonium chloride preferably the latter. Suitable basesinclude tertiary amines, sodium hydrogen carbonate, and sodiumcarbonate. The preferred base is triethylamine. The reaction isconducted at a temperature of from about 60° C. to about 180° C.,preferably from about 80° C. to 100° C.

Compounds of formula IB (R₁ =--CH₃) are prepared by hydride reduction ofa compound of the formula II where n, A, W, X, Y, Z, R₂, R₃, R₄ and R₅are as defined above, and R₁₃ is selected from C₁ -C₆ alkyl, aryl, andalkylaryl (preferably benzyl) with a hydride reducing agent in an inertsolvent. Suitable hydride reducing agents include lithium aluminumhydride, diborane, lithium borohydride, and sodium amide. The preferredreagent is lithium aluminum hydride. Suitable solvents include ethers,such as diethyl ether, tetrahydrofuran, 1,4-dioxane and1,2-dimethoxyethane. The preferred solvent is tetrahydrofuran. Thereduction is conducted at a temperature of from about 30° C. to about100° C., preferably from about 65° C. to about 70° C.

Compounds of formula IA (R₁ =H) are prepared by catalytic reduction of acompound of the formula II where n, A, W, X, Y, Z, R₂, R₃, R₄, R₅ andR₁₃ are as defined above under an atmosphere of hydrogen, preferably ata pressure of about 1 to about 3 atmospheres, or using a hydrogen sourcesuch as ammonium formate or formic acid in an inert solvent. Suitablecatalysts include palladium on carbon, Raney nickel, and platinum oxide.The preferred catalyst is palladium on carbon. Suitable solvents includeC₁ to C₆ alcohols, N,N-dimethylformamide, ethyl acetate, andacetonitrile. The preferred solvent is ethanol. The reaction isconducted at a temperature of from about 0° C. to about 60° C.,preferably about 25° C.

Compounds of formula IC (R₁ ≠H) are also prepared by the alkylation of acompound of the formula IA (R₁ =H) wherein R₂, R₃, R₄, R₅, R₁₁, W, X, Y,Z, A, and n are as defined above with an alkylating agent of the formulaR₁ -LG and a base in an inert solvent, where LG is a suitable leavinggroup and R₁ is as defined above except for hydrogen. Examples ofsuitable leaving groups include --I, --Br, --Cl, --OSO₂ Ph, --OSO₂ CH₃,and --OSO₂ CF₃. Suitable alkylating agents include alkyl halides(chlorides, bromides, or iodides), alkyl tosylates, alkyl mesylates,alkyl triflates, α,β-unsaturated ketones, α,β-unsaturated esters,α,β-unsaturated amides, and α,β-unsaturated nitriles. Alkyl halides(iodides) are preferred. Suitable solvents include methylene chloride,chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, diethylether, dioxane, N,N-dimethylformamide, ethanol, propanol, and methanol.The preferred solvent is acetonitrile. The reaction is conducted betweena temperature of about 0° C. to about 150° C., preferable about 25° C.to about 65° C.

Compounds of formula V are prepared via the following reaction scheme.##STR6##

Compounds of the formula VI can be prepared using the Witrig reaction ina suitable solvent involving compounds of the formulas VII and VIIIwherein n and R₁₃ are defined as above. R₁₆ is C₁ -C₆ alkyl, aryl, oralkylaryl. Suitable solvents include ethers such a diethyl ether,tetrahydrofuran, and 1,4-dioxane. Tetrahydrofuran is the preferredsolvent. The reaction is conducted at a temperature of from about -78°C. to about 30° C., preferably at about -78° C.

Compounds of the formula V can be prepared from a hydride reduction of acompound of formula VI wherein n, R₁₃ and R₁₆ are as defined above witha hydride reducing agent in an inert solvent. Suitable hydride reducingagents include lithium aluminum hydride, lithium borohydride, sodiumborohydride, and diisobutylaluminum hydride. The preferred reagent isdiisobutylaluminum hydride. Suitable solvents include ethers, such asdiethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. Thepreferred solvent is tetrahydrofuran. The reduction is conducted at atemperature of from about -100° C. to about 0° C., preferably from about-80° C. to about -70° C.

Compounds of the formula VII can be prepared using methods known to oneskilled in the art, such as, for example, as outlined in S. Kiyooka, etal., J. Org. Chem., 5409 (1989) and Y. Hamada, et al., Chem. Pharm.Bull., 1921 (1982).

Compounds of the formula VIII are either commercially available or canbe prepared using methods known to one skilled in the art, such as, forexample, as outlined in L. Fieser and M. Fieser, Reagents for OrganicSynthesis, John Wiley and Sons, New York, Vol. 1, p. 112 (1967).

Compounds of formula IV are prepared using the following reactionscheme. ##STR7##

Compounds of formula IX can be prepared by reacting a compound offormula XI wherein A, W, X, Y, Z, R₂, R₃, R₄ and R₅ are as defined abovewith either chlorine, bromine, or iodine in a suitable solvent with asuitable base. Reaction with bromine is preferred. Suitable solventsinclude C₁ -C₆ alcohols, methylene chloride, chloroform, or carbontetrachloride. The preferred solvent is methanol. Suitable bases includetriethylamine, pyridine, sodium carbonate, and sodium hydrogencarbonate. The preferred base is sodium hydrogen carbonate. The reactionis conducted at a temperature of from about 0° C. to about 65° C.,preferably at about 25° C.

Compounds of formula IV can be prepared by reacting a compound offormula IX wherein A, W, X, Y, Z, R₂, R₃, R₄, R₅, and R₁₄ are as definedabove with the acid chloride or symmetrical anhydride of the formula R₁₅CO₂ H in a suitable solvent with an suitable base. The preferred acidchloride or anhydride is trifluoroacetic anhydride. Suitable solventsinclude methylene chloride, chloroform as well as ethers, includingtetrahydrofuran, diethyl ether and 1,4-dioxane. The preferred solvent ismethylene chloride. Suitable bases include triethylamine, pyridine, andsodium hydrogen carbonate. The preferred base is pyridine. The reactionis conducted at a temperature of from about 0° C. to about 65° C.,preferably at about 25° C.

Compounds of the formula XI can be prepared using methods known to oneskilled in the art, such as, for example, as outlined in European PatentApplication Pub. No. 0 438 230 A2.

Compounds of formula IX where W is oxygen, X and Z are nitrogen, and Yis carbon can also be prepared by reacting together compounds of theformula ##STR8## wherein A, R₄, R₁₂ are as defined above, and R₁₇ is C₁-C₈ alkyl or aryl in an inert solvent in the presence of a base [P.Sauerberg, et al. J. Med. Chem., 687 (1991), G. A. Showell, J. Med.Chem., 1086 (1991) and European Patent Application Pub. No. 0 438 230A2]. Suitable solvents include ethers such as tetrahydrofuran,1,4-dioxane, and diethyl ether, methylene chloride, chloroform, carbontetrachloride, and C₁ -C₆ alcohols. The preferred solvent istetrahydrofuran. Suitable bases included sodium metal, sodium hydride,potassium hydride, and potassium t-butoxide. The preferred base issodium hydride. The reaction is conducted at a temperature of about 0°C. to 101° C., preferably at about 66° C.

Compounds of formula XII, if not commercially available, can be preparedvia the reaction of a compound of the formula ##STR9## wherein A and R₁₇are as defined above with either chlorine, bromine, or iodine in asuitable solvent with a suitable base. Reaction with bromine ispreferred. Suitable solvents include C₁ -C₆ alcohols, methylenechloride, chloroform, or carbon tetrachloride. The preferred solvent ismethanol. Suitable bases include triethylamine, pyridine, sodiumcarbonate, and sodium hydrogen carbonate. The preferred base is sodiumhydrogen carbonate. The reaction is conducted at a temperature of about0° C. to about 65° C., most preferably at about 25° C.

Compounds of the formula XIII can be prepared using methods known to oneskilled in the art, such as, for example, C. L. Bell, et al. J. Org.Chem., 2873 (1964).

Compounds of formula XIV are available either commercially or usingmethods known to one skilled in the art, such as, for example, E.Ferber, et al., Chem. Ber., 839 (1939).

The compounds of the formula I which are basic in nature, are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, i.e.,where R₂ contains a carboxylate, are capable of forming base salts withvarious pharmacologically acceptable cations. Examples of such saltsinclude the alkali metal or alkaline-earth metal salts and particular,the sodium and potassium salts. These salts are all prepared byconventional techniques. The chemical bases which are used as reagentsto prepare the pharmaceutically acceptable base salts of this inventionare those which form non-toxic base salts with the herein describedacidic compounds of formula I. These non-toxic base salts include thosederived from such pharmacologically acceptable cations as sodium,potassium, calcium, magnesium, etc. These salts can easily be preparedby treating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmacologically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they may also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction of maximum product of yields of the desiredfinal product.

The compounds of the formula I and the pharmaceutically acceptable saltsthereof (hereinafter, also referred to as the active compounds of theinvention) are useful psychotherapeutics and are potent serotonin(5-HT₁) agonists and may be used in the treatment of depression,anxiety, eating disorders, obesity, drug abuse, cluster headache,migraine, chronic paroxysmal hemicrania and headache associated withvascular disorders, pain, and other disorders arising from deficientserotonergic neurotransmission. The compounds can also be used ascentrally acting antihypertensives and vasodilators. The activecompounds of the invention can be evaluated as anti-migraine agents bytesting the extent to which they mimic sumatriptan in contracting thedog isolated saphenous vein strip [P. P. A. Humphrey et al., Br. J.Pharmacol., 94, 1128 (1988)]. This effect can be blocked bymethiothepin, a known serotonin antagonist, Sumatriptan is known to beuseful in the treatment of migraine and produces a selective increase incarotid vascular resistance in the anesthetized dog. It has beensuggested [W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989)] thatthis is the basis of its efficacy.

The serotonin 5-HT₁ agonist activity can be measured in in vitroreceptor binding assays as described for the 5-HT_(1A) receptor usingrat cortex as the receptor source and [³ H]-8-OH-DPAT as the radioligand[D. Hoyer et al. Eur. J. Pharm., Vol. 118, 13 (1985)] and as describedfor the 5-HT_(1D) receptor using bovine caudate as the receptor sourceand [³ H]serotonin as the radioligand [R. E. Heuring and S. J. Peroutka,J. Neuroscience, Vol. 7, 894 (1987)] 5-HT₁. agonist activity is definedby agents with affinities (IC₅₀ 's) of 250 nM or less at either bindingassay.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycolate);or wetting agents (e.g. sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., migraine) is 0.1 to200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult are preferably arranged so thateach metered dose or "puff" of aerosol contains 20 μg to 1000 μg of thecompound of the invention. The overall daily does with an aerosol willbe within the range 100 μg to 10 mg. Administration may be several timesdaily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3doses each time.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (d) and are referenced to the deuteriumlock signal from the sample solvent. Specific rotations were measured atroom temperature using the sodium D line (589 nm). Unless otherwisestated, all mass spectrum were performed using electron impact (EI, 70eV) conditions.

Commercial reagents were utilized without further purification.Chromatography refers to column chromatography performed using 32-63 μmsilica gel and executed under nitrogen pressure (flash chromatography)conditions. Room temperature refers to 20°-25° C.

EXAMPLE 1 General Procedure for the Hydride Reduction of3-(N-Benzyloxycarbonyl-pyrrolidin -2-ylmethyl)-1H-indoles Forming3-(N-Methylpyrrolidin-2-ylmethyl)-1H-indoles

To a stirred mixture of lithium aluminum hydride (0.152 g, 4.00 mmol, 2eq.) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added rapidly asolution of the 3-(N-benzyloxycarbonyl-pyrrolidin-1-ylmethyl)-1H-indole(2.00 mmol) in anhydrous tetrahydrofuran (5 mL). The resulting mixtureis heated at reflux under a nitrogen atmosphere for 3 hours. Thereaction mixture is cooled, and water (0.25 mL), 15% aqueous sodiumhydroxide (0.25 mL), and then more water (0.75 mL) were addedsequentially. The resulting mixture was stirred at 25° C. for 30minutes, filtered, and the filtrate was evaporated under reducedpressure. The residue was column chromatographed using silica gel(approximately 50 g) and elution with a solution methylene chloride:methanol: ammonium hydroxide [9:1:0.1] or other appropriate solventsystem to afford the corresponding 3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.

Following this procedure the following compounds were prepared:

A. (R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-5-(4-Benzyl-1,3-thiazol-2-yl)-3-(N-benzyloxycarbonylpyrrolidin-2-yl-methyl)-1H-indole was used. Chromatography using 5% triethylamine in ethylacetate afforded the title compound (71%) as a white solid: top,146.0°-148.0° C.; ¹³ C NMR (CDCl₃) 67 169.8, 157.1, 139.3, 137.3, 129.2,128.5, 128.0, 126.4, 125.7, 123.2, 121.2, 117.6, 114.8, 113.2, 111.5,66.6, 57.5, 40.8, 38.1, 31.4, 29.6, 21.9; LRMS (m/z, relative intensity)387 (M⁺, 4), 303 (34), 155 (30), 147 (17), 115 (18), 85 (63), 84 (100),83 (57); [α]²⁵ =+68° (CHCl₃, c=1.0). Anal. calcd. for C₂₄ H₂₅ N₃ S·1/4H₂O: C, 73.54; H, 6.56; N, 10.72. Found: C, 73.50; H, 6.53; N, 10.57.

B.(R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-5-(3-Benzyl-1,2,4-oxadiazol-5-yl)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole was used. Column chromatography as described above affordedthe title compound (34%) as a tan solid: ¹ H NMR (CDCl₃) δ 8.48 (s, 1H),8.36 (s, 1H), 7.91 (dd, J=8 and 2 Hz, 1H), 7.43-7.25 (m, 6H), 7.12 (s,1H), 4.13 (s, 2H), 3.28-(m, 2H), 2.77-2.68 (m, 1H), 2.53 (m, 1H), 2.46(s, 3H), 2.26 (q, J=8 Hz, 1H), 1.92-1.74 (m, 2H), 1.74-1.54 (m, 2H);HRMS, calculated for C₂₃ H₂₄ N₄ O 372.1945, found 372.1978.

C.(R)-5-(3-benzyl,1,2,4-oxadiazol-5-ylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole

(R)-5-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole was used. Column chromatography as describedabove afforded the title compound (24%) as a beige resin: ¹ H NMR(CDCl₃) δ 8.10 (br s, 1H), 7.47 (s, 1H), 7.34-7.18 (m, 6H), 7.08 (dd,J=8 and 2 Hz, 1H), 7.04 (br s, 1H), 4.25 (s, 2H), 4.01 (s, 2H),3.22-3.07 (m, 2H), 2.66-2.55 (m, 1H), 2.54-2.43 (m, 1H), 2.42 (s, 3H),2.24 (q, J=8 Hz, 1H), 1.86-1.69 (m, 2H), 1.68-1.50 (m, 2H); HRMScalculated for C₂₄ H₂₆ N₄ O 386.2070, found 386.2074.

EXAMPLE 2 General Procedure for the Catalytic Reduction of3-(N-Benzyloxycarbonyl-pyrrolidin -2-ylmethyl)-1H-indoles Forming3-(Pyrrolidin-2-ylmethyl)-1H-indoles

A mixture of the 3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole(2.00 mmol) and 10% palladium on carbon (0.20 g) in absolute ethanol (15mL) was shaken under a hydrogen atmosphere (3 atm) for 4-24 hours,depending on substrate. The resulting reaction mixture was filteredthrough diatomaceous earth, and the filtrate was evaporated underreduced pressure. The residue was column chromatographed using silicagel (approximately 10 g) and elution with a solution of methylenechloride: methanol:ammonium hydroxide [8: 2: 0.2] or other appropriatesolvent system to afford the corresponding3-(pyrrolidin-2-ylmethyl)-1H-indole.

Following this procedure the following compounds were prepared:

A. (R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(pyrrolidin-2-ylmethyl)-1H-indole

(R)-5-(4-Benzyl-1,3-thiazol-2-yl)-3-(N-benzyloxycarbonylpyrrolidin-2-yl-methyl)-1H-indolewas used, and the reaction was heated at 40° C. for 24 hours.Chromatography using methylene chloride:methanol:ammonium hydroxide[9:1:0.1] afforded the title compound (12%) as an amorphous solid: ¹ HNMR (CDCl₃) δ 9.1 (br s, indole NH), 8.17 (d, J=1.4 Hz, 1H), 7.74 (dd,J=1.6 and 8.5 Hz, 1H), 7.35-7.21 (m, 6H), 7.02 (s, 1H), 6.67 (s, 1H),4.22 (s, 2H), 3.5 (br s, NH), 3.41-3.29 (m, 1H), 3.03-2.73 (m, 4H),1.94-1.61 (m, 3H), 1.49-1.38 (m, 1H); ¹³ C NMR (CDCl₃)δ 169.9, 157.0,139.2, 137.4, 129.2, 128.5, 127.7, 126.4, 125.5, 123.8, 121.2, 117.3,114.3, 113.3, 111.7, 59.2, 46.0, 38.1, 31.5, 31.1, 24.9; HRMS calculatedfor C₂₃ H₂₃ N₃ S 374.1615, found 374.1691.

EXAMPLE 3 General Procedure for the Formation of3-(N-Benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indoles Via thePalladium Catalyzed Cyclization of1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)-propenes

A mixture of the1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetylamino)propene(2.00 mmol), tetrabutylammonium chloride (2.00 mmol), and palladium(II)acetate (0.089 g, 0.40 mmol, 0.2 eq) in a solution of triethylamine (8mL) and anhydrous N,N-dimethylformamide (4 mL) was heated at refluxunder nitrogen for 2 hours. The resulting reaction mixture wasevaporated under reduced pressure, and the residue was partitionedbetween ethyl acetate (25 mL) and water (25 mL). The ethyl acetate layerwas removed, and the aqueous layer was extracted with ethyl acetate (25mL). The organic extracts were combined, dried (M_(g) SO₄), andevaporated under reduced pressure. The residue was columnchromatographed using silica gel (approximately 50 g) and elution with40% ethyl acetate in hexanes or an appropriate solvent system to affordthe corresponding 3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole.

Following this procedure the following compounds were prepared:

A.(R)-5-(4-Benzyl-1,3-thiazol-2-yl)-3-(N-benzyloxycarbonylpyrrolidin-2-yl-methyl)-1Hindole

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-(4-benzyl-1,3-thiazol-2-yl)phenyl)-N-trifluoroacetylamino)propenewas used. Chromatography using elution with ethyl acetate gradient inhexanes [1:3 to 2:5] afforded the title compound (58%) as a pale yellowfoam: FAB LRMS (m/z, relative intensity) 509 (MH⁺, 37), 508(M⁺, 100),462 (5), 372 (8), 304 (33); FAB HRMS calculated for [C₃₁ H₃₀ N₃ O₂ S·H]⁺509.2139, found 509.2106. Anal. calcd for C₃₁ H₃₀ N₃ O₂ S·1/2 C₄ H₈ O₂[ethyl acetate]: C, 71.71; H, 6.20; N, 7.60. Found: C, 71.55: H, 5.82;N, 7.64.

B.(R)-5-(3-Benzyl-1,2,4-oxadiazol-5-yl)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-1H-indole

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-(3-benzyl-1,2,4-oxadiazol-5-yl)phenyl)-N-trifluoroacetylamino)propenewas used. Column chromatography using the above described solvent systemafforded the title compound (74%) as a light yellow resin: R₁ =0.41(hexane-EtOAc 50:50); HRMS calculated for C₃₀ H₂₉ N₄ O₃ 493.2288, found:493.2240.

C.(R)-5-(3-Benzyl-1,2,4,-oxadiazol-5-ylmethyl)-3-(N-benzyloxycarbonylpyrrolidin-2-yl-methyl)-1H-indole

(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)phenyl)-N-trifluoroacetylamino)propenewas used. Column chromatography using the above described solvent systemafforded the title compound (61%) as a tan resin: R₁ =0.063(hexane-EtOAc 50:50); HRMS calculated for C₃₁ H₃₁ N₄ O₃ 507.2396, found:507.2387.

EXAMPLE 4 General Procedure for the Formation1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-2-halophenyl)-N-trifluoroacetylamino)propenesfrom the Mitsunobu Coupling of 2-Halo -N-trifluoroacetylanilines with1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene

To a stirred solution of1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene (R, or S, orracemate, 2.00 mmol), the 2-halo-N-trifluoroacetylaniline (2.5 mmol,1.25 eq), and triphenylphosphine (0.655 g, 2.50 mmol, 1.25 eq) inanhydrous tetrahydrofuran (15 mL) at 0° C. under a nitrogen atmospherewas added diethyl azodicarboxylate (0.39 mL, 2.48 mmol, 1.25 eq)dropwise. The reaction solution was slowly warmed to 25° C. over thecourse of 2 hours, and then stirred at 25° C. under a nitrogenatmosphere for an additional 12 hours. The resulting reaction solutionwas evaporated under reduced pressure, and the residue was columnchromatographed using silica gel (approximately 150 g) and elution withan appropriate solvent system to afford the corresponding 1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-halophenyl)-N-trifluoroacetyl-amino)propene.

Following this procedure the following compounds were prepared:

A.(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-(4-benzyl-1.3-thiazol-2-yl)phenyl)-N-trifluoroacetylamino)propene

4-(4-Benzyl-1,3-thiazol-2-yl)-2-bromo-1-trifluoroacetylaminobenzene and(R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used.Chromatography using elution with a 1-5% either gradient in methylenechloride afforded the title compound (97%) as a white foam: FAB LRMS(m/z, relative intensity) 686 (MH₂ ⁺, 100), 685 (MH⁺, 60), 684 (M⁺, 90),640 (23), 578 (15), 441 (17), 371 (20); FAB HRMS calculated for [C₃₃ H₂₉BrF₃ N₃ O₃ S·H]⁺ [with ⁷⁸ Br and ³² S] 664.1145, found 684.1157.

B.(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-(3-benzyl-1,2,4-oxadiazol-5-yl)phenyl)-N-trifluoroacetylamino)propene

4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-2-bromo-1-trifluoroacetylaminobenzeneand (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene wereused. Chromatography using elution with 5% either in methylene chlorideafforded the title compound (88%) as a thick yellow oil: R₁ =0.32(CHCl₃); LRMS (m/z, relative intensity) 669 (M+, 25).

C.(R)-1(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-(N-(2-bromo-4-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)phenyl)-N-trifluoroacetylamino)propene

4-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromo-1-trifluoroacetylaminobenzeneand (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene wereused. Chromatography using elution with 5% either in methylene chlorideafforded the title compound (90%) as a thick yellow oil: R₁ =0.75 (CHCl₃--CH₃ OH 20:1); LRMS (m/z, relative intensity) 683 (M+,18).

EXAMPLE 5 (R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene

To a stirred solution of ethyl(R)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (3.03 g, 10.00mmol) in anhydrous tetrahydrofuran (75 mL) at -78° C. under nitrogen wasadded dropwise a solution of diisobutylaluminum hydride (1.0M inhexanes, 22.0 mL, 22.0 mmol, 2.2 eq). The resulting solution was stirredat -78° C. under nitrogen for 30 minutes. The reaction solution was thenallowed to warmed to room temperature over the course of 2 hours. Asaturated solution of sodium hydrogen carbonate (50 mL) was added, andthe aqueous mixture was extracted with ethyl acetate (3×50 mL). Theextracts were combined, dried (MgSO₄), and evaporated under reducedpressure. Column chromatography of the residue with an diethylether/hexanes [1:1] afforded the title compound as a clear colorless oil(1.41 g, 5.40 mmol, 54%): ¹ H NMR (CDCl₃) δ 7.40-7.25 (m, 5H), 5.75-5.53(m, 2H), 5.20-5.00 (m, 2H), 4.38 (br m, 1H), 4.06 (br d, J=13.7 Hz, 3H),3.45 (br t, J=7.0 Hz, 1H), 2.03-1.68 (m, 4H); [a]²⁵ =+34° (MeOH, c=1.0);HRMS calculated for C₁₅ H₁₉ NO₃ 261.1365, found 261.1356.

EXAMPLE 6 Ethyl (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate

To a stirred solution of N-carbobenzyloxypyrrolidine-2-carboxaldehyde(1.17 g, 5.00 mmol) in anhydrous tetrahydrofuran at -78° C. was added(carboethoxymethylene)triphenylphosphorane (2.09 g, 6.00 mmol. 1.2 eq)as a solid portionwise. The resulting reaction mixture was stirred atroom temperature under nitrogen for 2 hours, and then heated at refluxunder nitrogen for 1 hour. The reaction mixture was evaporated underreduced pressure and the residue was column chromatographed using silicagel (approximately 100 g) and elution with 20% diethyl ether in hexanesto afford the title compound as a clear, colorless oil (1.11 g, 3.65mmol, 73%): ¹ H NMR (CDCl₃) δ 7.34-7.25 (m, 5H), 6.89-6.76 (m, 1H),5.88-5.74 (m, 1H), 5.18-5.05 (m, 2H), 4.60-4.43 (m, 1H), 4.17 (q, J=7.1Hz, 2H), 3.55-3.40 (m, 2H), 2.11-2.00 (m, 1H), 1.90-1.75 (m, 3H), 1.28(t, J=7.1 Hz, 3H); ¹³ C NMR (CDCl₃) [Note: due to slow nitrogeninversion two conformers of the products are seen by NMR spectroscopy] δ166.3, 154.7, 147.9, 147.4, 136.6, 128.4, 127.9, 120.9, 66.9, 65.8,60.4, 58.1, 57.7, 46.8, 46.4, 31,6, 30.8, 23.6, 22.8, 22.6, 15.3, 14.2.

EXAMPLE 7 General Synthesis of 2-Halo-N-trifluoroacetylanilines fromReaction of 2-Haloanilines and Trifluoroacetic Anhydride

To a stirred solution of the 2-haloaniline (2.00 mmol) and pyridine(0.18 mL, 2.22 mmol, 1.1 eq) in anhydrous methylene chloride (10 mL) at0° C. under a nitrogen atmosphere was added dropwise trifluoroaceticanhydride (0.31 mL, 2.19 mmol, 1.1 eq). The resultant reaction mixturewas stirred at 0° C. under a nitrogen atmosphere for 3 hours. Asaturated solution of sodium hydrogen carbonate was added (15 mL), andthis aqueous mixture was extracted with ethyl acetate (3×15 mL). Theextracts were combined, dried (MgSO₄), and evaporated under reducedpressure. If necessary, the residue was column chromatographed usingsilica gel (approximately 50 g) and elution with an ethyl acetategradient in hexanes to afford the corresponding2-halo-N-trifluoroacetylaniline.

Following this procedure the following compounds were prepared:

A. 4-(4-Benzyl-1,3-thiazol-1-yl)-2-bromo-1-trifluoroacetylaminobenzene

4-(4-Benzyl-1,3-thiazol-2-yl)-2-bromoaniline was used. The extractionresidue was triturated in diethyl ether/hexanes [1:1, 10 mL] to affordthe title compound (92%) as a white powder: top, 102.0°-104.0° C.; ¹³ CNMR (CDCl₃) δ 164.9, 158.0, 138.7, 134.1, 132.6, 130.1, 129.1, 128.6,126.8, 126.6, 121.8, 115.2, 114.4, 38.0. Anal. calcd for C₁₈ H₁₂ F₃ BrN₂OS: C, 48.99; H, 2.74; N, 6.35. Found: 48.72; H, 2.58; N, 6.29.

B.4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-2-bromo-1-trifluoroacetylaminobenzene

4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-2-bromoaniline was used. Columnchromatography as described above afforded the title compound (81%) as awhite solid: mp, 152.0°-153.0° C.; ¹ H NMR (CDCl₃) δ 8.64 (br s, 1H),8.53 (d, J=8 Hz, 1H), 8.83 (d, J=2 Hz, 1H), 8.13 (dd, J=8 and 2 Hz, 1H),7.40-7.26 (m, 5H), 4.14 (s, 2H); LRMS (m/z, relative intensity) 426(M+,85).

C.4-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromo-1-trifluoroacetylaminobenzene

4-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromoaniline was used. Columnchromatography as described above afforded the title compound (90%) as ayellow resin: ¹ H NMR (CDCl₃) δ 8.59 (br s, 1H); 8.36 (br s, 1H), 8.22(d, J=8 Hz, 1H), 7.42 (s, 1H), 7.24-7.32 (m, 5H), 4.10 (s, 2H), 4.01 (s,2H); LRMS (m/z, relative intensity) 440 (M+,90).

EXAMPLE 8 4-(4-Benzyl-1,3-thiazol-2-yl)-2-bromoaniline

A mixture of 4-amino-3-bromobenzthioamide (1.66 g, 7.18 mmol) and1-chloro-3-phenylacetone [Tarhouni, R. et al., Tetrahedron Letters, 835(1964)] (1.36 g, 8.07 mmol, 1.1 eq) in absolute ethanol (18 mL) washeated at reflux under nitrogen for 2.5 hours. The resulting reactionmixture was evaporated under reduced pressure, and the residue waspartitioned between ethyl acetate (20 mL) and a saturated solution ofsodium hydrogen carbonate (20 mL). The ethyl acetate layer was removed,and the aqueous layer was extracted with ethyl acetate (2×20 mL). Theorganic extracts were combined, dried (MgSO₄), and evaporated underreduced pressure. The residual solid was chromatographed using silicagel (approximately 175 g) and elution with an ethyl acetate gradient inhexanes [1:4 to 1:1] to afford the title compound (68%) as a pale yellowsolid: top, 110°-115° C.; ¹³ C NMR (CDCl₃) δ 166.8, 157.1, 145.6, 139.1,130.7, 129.1, 128.6, 126.9, 126.4, 125.4, 115.3, 113.2, 109.2, 38.0.Anal. calcd for C₁₆ H₁₃ BrN₂ S: C, 55.66; H, 3.79; N, 8.11. Found: C,55.36; H, 3.71; N, 7.92.

EXAMPLE 9 4-Amino-3-Bromobenzthioamide

A stirred solution of 4-amino-3-bromobenzonitrile (6.92 g, 35.1 mmol)and diethyl dithiophosphate (17.7 mL, 105 mmol, 3 eq.) in absoluteethanol (160 mL) at 0° C. was perfused with hydrogen chloride gas at amoderate rate for 30 minutes. The resulting reaction mixture was stirredat room temperature for 12 hours, and then solvent was removed viaevaporation under reduced pressure. The residue was suspended in asaturated solution of sodium hydrogen carbonate (25 mL), and thisaqueous mixture was extracted with ethyl acetate (3×25 mL). The organicextracts were combined, dried (MgSO₄), and evaporated under reducedpressure. The residue was chromatographed using silica gel(approximately 300 g) and elution with an acetone gradient in methylenechloride [1:50 to 1:20] to afford the title compound (1.02 g, 25%) as anamorphous yellow solid: ¹ H NMR (DMSO-d₆) δ 9.41 (br s, NH), 9.13 (br s,NH), 9.13 (br s, NH), 8.11 (d, J=2.1 Hz, 1H), 7.78 (dd, J=2.1 and 8.6Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.03 (s, 2NH); TLC: RB₁ =0.15[1%diethyl ether in methylene chloride].

EXAMPLE 10 General Procedure for the Formation of2-Halo-4-(1,2,4-oxadiazol-5-yl)anilines or2-Halo-4-(1,2,4-oxadiazol-5-ylmethyl)anilines from the Condensation ofthe Corresponding Alkyl 4-Amino-3-halobenzoates or Alkyl2-(4-Amino-3-halophenyl)acetates, respectively, with PhenylacetamideOxime

Sodium hydride (87 mg of an 60% oil dispersion, 2 mmol) was added to astirred solution of phenylacetamide oxime (0.33 g, 2.2 mmol, 1.1 eq) [C.L. Bell, et al., J. Org. Chem., 2873 (1964)] in anhydrous THF (10 ml),and the resulting reaction mixture was heated at reflux for 30 minutes.A solution of the alkyl 4-amino-3-halobenzoate or alkyl2-(4-amino-3-halophenyl)acetate (1 mmol) in anhydrous THF (5 mL) wasthen added, and the reaction was heated under reflux for 2 hours. Themixture was allowed to cool to room temperature before water (10 ml) wasadded. The resulting aqueous mixture was extracted with dichloromethane(3×25 ml). The extracts were combined, dried (MgSO₄), and evaporatedunder reduced pressure. The residue was chromatographed using silica gel(20 g) and elution with chloroform to afford the corresponding2-halo-4-(1,2,4-oxadiazol-5-yl)aniline or2-halo-4-(1,2,4-oxadiazol-5-ylmethyl)aniline, respectively.

Following this procedure the following compounds were prepared:

A. 4-(3-Benzyl-1,2,4-Oxadiazol-5-yl)-2-bromoaniline

Methyl 4-amino-3-bromobenzoate was used. Column chromatography asdescribed above afforded the title compound (33%) as a tan solid; mp144°-145° C.; ¹ H NMR (CDCl₃) δ 8.18 (d, J=2 Hz, 1H), 7.82 (dd, J=8 and2 Hz, 1H), 7.39-7.25 (m, 5H), 6.77 (d, J=8 Hz, 1H), 4.09 (s, 2H); LRMS(m/z, relative intensity) 330 (M+,90).

B. 4-(3-Benzyl-1,2,4-oxadiazol-5-ylmethyl)-2-bromoaniline

Ethyl 2-(4-amino-3-bromophenyl)acetate was used. Column chromatographyas described above afforded the title compound (41%) as a yellow resin;¹ H NMR (CDCl₃) δ 7.34-7.24 (m, 6H), 7.00 (dd, J=8 and 2 Hz, 1H), 6.69(d, J=8 Hz, 1H), 4.02 (s, 2H), 4.01 (s, 2H); LRMS (m/z, relativeintensity) 334 (M+,15).

EXAMPLE 11 General Procedure for the Bromination of Anilines to Form2-Bromoanilines

To a stirred mixture of the aniline (2.00 mmol) and sodium hydrogencarbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. wasadded dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resultingreaction mixture was then stirred at 25° C. for 30 minutes. The reactionmixture was then evaporated under reduced pressure, and the residue wasplaced in a saturated solution of sodium hydrogen carbonate (10 mL).This aqueous mixture was extracted with ethyl acetate (3×15 mL). Theextracts were combined, dried (MgSO₄), and evaporated under reducedpressure. The residue was column chromatographed using silica gel(approximately 50 g) and elution with an appropriate solvent system toafford the corresponding 2-bromoaniline.

Following this procedure the following compounds were prepared:

A. 4-Amino-3-bromobenzonitrile

4-Aminobenzonitrile was used. Chromatography using elution with agradient of ethyl acetate in hexanes [1:5 to 1:3] afforded the titlecompound (71%) as a white solid: ¹ H NMR (CDCl₃) δ 7.65 (d, J=2.1 Hz,1H), 7.34 (dd, J=2.1 and 8.1 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 4.6(br s,2NH); TLC:R₁ =0.25 [ethyl acetate/hexanes, 1:3].

B. Methyl 4-amino-3-bromobenzoate

Methyl 4-aminobenzoate was used. Chromatography using elution with ethylacetate in hexanes [1:4] afforded the title compound (36%) as an orangeoil: ¹ H NMR (CDCl₃) δ 8.09 (d, J=2 Hz, 1H), 7.75 (dd, J=9 and 2 Hz,1H), 6.71 (d, J=9 Hz, 1H), 4.49 (br s, 2H), 3.84 (s, 3H); HRMS (m/z,relative intensity) 230 (M+,100).

C. Ethyl 2-(4-amino-3-bromophenyl)acetate

Ethyl 2-(4-aminophenyl)acetate was used. Chromatography using elutionwith ethyl acetate in hexanes [1:4] afforded the title compound (25%) asa light brown oil: ¹ H NMR (CDCl₃) δ 7.33 (d, J=2 Hz, 1H), 7.02 (dd, J=8and 2 Hz, 1H), 6.76 (dd, J=8Hz, 1H), 4.11 (q, J=7 Hz, 2H), 3.45 (s, 2H),1.23 (t, J=7 Hz, 3H); LRMS (m/z, relative intensity) 258 (M +,100).

We claim:
 1. A compound of the formula ##STR10## where A represents adirect bond, C₁ -C₄ alkylene, or C₁ -C₄ alkenylene; n is 0, 1, or 2; R₁is hydrogen, C₁ -C₆ alkyl, aryl, C₁ -C₃ alkylaryl, C₁ -C₃alkylheteroaryl, or --(CH₂)_(m) R₆ ; W, X, Y, and Z are eachindependently oxygen, sulfur, nitrogen or carbon, provided that at leastone of W, X, Y or Z is nitrogen; R₂, R₃, R₄, and R₅ are eachindependently hydrogen. C₁ -C₆ alkyl, aryl, C₁ -C₃ alkylaryl, C₁ -C₃alkylheteroaryl, halogen, cyano, trifluoromethyl, nitro, --OR₇, --NR₇R₈, --(CH₂)_(s) OR₇, --SR₇, --SO₂ NR₇ R₈, --NR₇ SO₂ R₈, --NR₇ CO₂ R₈,--CONR₇ R₈, or --CO₂ R₇ ; one of R₂ and R₃, R₃ and R₄, or R₄ and R₅ maybe taken together to form a five- to seven-membered alkyl ring, asix-membered aryl ring, a five- to seven-membered heteroalkyl ringhaving 1 heteroatom of N, O, or S, or a five- to six-membered heteroarylring having 1 or 2 heteroatoms of N, O, or S; R₆ is cyano,trifluoromethyl, or --OR₉ ; R₇, R₈, and R₉ are each independentlyhydrogen, C₁ to C₆ alkyl, --(CH₂)_(m) R₁₀, C₁ to C₃ alkylaryl, or aryl;R₇ and R₈ may be taken together to form a C₄ -C₇ alkyl ring; R₁₀ iscyano, trifluoromethyl, or C₁ -C₄ alkoxy; R₁₁ is hydrogen, --OR₁₂, or--NCHOR₁₂ ; R₁₂ is C₁ to C₆ alkyl, aryl, or C₁ to C₃ alkyl-aryl; m is 1,2, or 3; s is 0, 1, 2, or 3; and the above aryl groups and the arylmoieties of the above alkylaryl groups are independently selected fromphenyl and substituted phenyl, wherein said substituted phenyl may besubstituted with one to three groups selected from C₁ to C₄ alkyl,halogen, hydroxy, cyano, carboxamido, nitro, and C₁ to C₄ alkoxy, andthe pharmaceutically acceptable salts thereof.
 2. A compound accordingto claim 1, wherein the compound of Formula I is ##STR11##
 3. A compoundaccording to claim 2, wherein the compound is the cis epimer.
 4. Acompound according to claim 1 wherein A is a direct bond or --CH₂ --; nis 1; R₁ is hydrogen, C₁ -C₄ alkyl, or --CH₂ CH₂ OCH₃ ; Z is nitrogen; Yis carbon; W and X are each independently oxygen, sulfur, nitrogen orcarbon; R₁₁ is hydrogen or --OCH₃.
 5. A compound according to claim 4,wherein the compound of Formula I is ##STR12##
 6. A compound accordingto claim 5, wherein the compound is the cis epimer.
 7. A compoundaccording to claim 1, said compound being selectedfrom(R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(4-benzyl-1,3-thiazol-2-yl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(3-benzyl-1,2,4-oxadiazol-5-yl)-3-(pyrrolidin-2-ylmethyl)-1H-indole;(R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole;and(R)-5-(3-benzyl-1,2,4-oxadiazol-5-ylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole.8. A pharmaceutical composition for treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain, and chronic paroxysmalhemicrania and headache associated with vascular disorders comprising anamount of a compound according to claim 1 effective in treating suchcondition and a pharmaceutically acceptable carrier.
 9. A pharmaceuticalcomposition for treating disorders arising from deficient serotonergicneurotransmission comprising an amount of a compound according to claim1 effective in treating such a disorder and a pharmaceuticallyacceptable carrier.
 10. A method of treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain, and chronic paroxysmalhemicrania and headache associated with vascular disorders comprisingadministering to a mammal requiring such treatment an amount of acompound according to claim 1 effective in treating such condition. 11.A method for treating disorders arising from deficient serotonergicneurotransmission comprising administering to a mammal requiring suchtreatment an amount of a compound according to claim 1 effective intreating such condition.
 12. A compound of the formula ##STR13## where Arepresents a direct bond, C₁ -C₄ alkyl, or C₁ -C₄ alkenyl; n is 0, 1, or2; W, X, Y, and Z are each independently oxygen, sulfur, nitrogen orcarbon, provided that at least one of W, X, Y or Z is nitrogen; R₂, R₃,R₄, and R₅ are each independently hydrogen, C₁ -C₆ alkyl, aryl, C₁ -C₃alkylaryl, C₁ -C₃ alkylheteroaryl, halogen, cyano, trifluoromethyl,nitro,--O₇, --NR₇ R₈, --(CH₂)_(s) OR₇, --SR₇, --SO₂ NR₇ R₈, --NR₇ SO₂R₈, --NR₇ CO₂ R₈, --CONR₇ R₈, or --CO₂ R₇ ; one of R₂ and R₃, R₃ and R₄,or R4 and R₅ may be taken together to form a five- to seven-memberedalkyl ring, a six-membered aryl ring, a five- to seven-memberedheteroalkyl ring having 1 heteroatom of N, O, or S, or a five- tosix-membered heteroaryl ring having 1 or 2 heteroatoms of N, O, or S; R₇and R₈ are each independently hydrogen, C₁ to C₆ alkyl, --(CH₂)_(m) R₁₀,C₁ to C₃ alkylaryl, or aryl; R₇ and R₈ may be taken together to form aC₄ -C₇ alkyl ring; R₁₀ is cyano, trifluoromethyl, or C₁ -C₄ alkoxy; m is1, 2, or 3; s is 0, 1, 2, or 3; R₁₁ is hydrogen, --OR₁₂, or --NHCOR₁₂ ;R₁₂ is C₁ to C₆ alkyl, aryl, or C₁ to C₃ alkyl-aryl; R₁₃ is C₁ -C₆alkyl, aryl, or alkylaryl; and the above aryl groups and the arylmoieties of the above alkylaryl groups are independently selected fromphenyl and substituted phenyl wherein said substituted phenyl may besubstituted with one to three groups selected from C₁ to C₄ alkyl,halogen, hydroxy, cyano, carboxamido, nitro, and C₁ to C₄ alkoxy.
 13. Acompound according to claim 12, wherein the compound of formula II is##STR14##
 14. A compound according to claim 13, wherein the compound isthe cis epimer.
 15. The compound of claim 12, wherein A is a direct bondor --CH₂ --; n is 1, Z is nitrogen; Y is carbon; W and X are eachindependently oxygen, sulfur, nitrogen or carbon; R₁₁ is hydrogen or--OCH₃.
 16. A compound according to claim 15, wherein the compound offormula II is ##STR15##
 17. A compound according to claim 16, whereinthe compound is the cis epimer.